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The C-46 was developed from the new and unproven commercial aircraft design, the CW-20, which first flew in March 1940. Deliveries of the AAF C-46s began in July 1942 for the Air Transport Command and Troop Carrier Command. During WW II, the AAF accepted 3,144 C-46s for hauling cargo, personnel and for towing gliders.

The C-46 gained its greatest fame during WW II transporting war materials over the "Hump" from India to China after the Japanese had closed the Burma Road. C-46 flights on the treacherous air route over the Himalayas began in May 1943. The Commando carried more cargo than the famous C-47 and offered better performance at higher altitudes, but under these difficult flying conditions, C-46s required extensive maintenance and had a relatively high loss rate. In Europe, C-46s dropped paratroopers during the aerial crossing of the Rhine River near Wesel in March 1945. C-46s saw additional service during the Korean War.